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Print version ISSN 0034-7094On-line version ISSN 1806-907X
Rev. Bras. Anestesiol. vol.55 no.5 Campinas Sept./Oct. 2005
Myocardial protection in cardiac surgery*
Protección miocárdica en cirugía cardiaca
Luiz Marcelo Sá Malbouisson, TSA, M.D.I; Luciana Moraes dos Santos, M.D.II; José Otávio Costa Auler Jr, TSA, M.D.III; Maria José Carvalho Carmona, TSA, M.D.IV
IDoutor em Ciências pela Universidade
de São Paulo. Especialista em Terapia Intensiva, AMIB. Médico Assistente
do Serviço de Anestesiologia e Terapia Intensiva Cirúrgica do Instituto
do Coração (InCor), HCFMUSP
IIPós-Graduanda da Disciplina de Anestesiologia da FMUSP. Médica Assistente do Serviço de Anestesiologia e Terapia Intensiva Cirúrgica do Instituto do Coração (InCor), HCFMUSP
IIIProfessor Titular da Disciplina de Anestesiologia da Faculdade de Medicina da Universidade de São Paulo. Especialista em Terapia Intensiva, AMIB. Diretor do Serviço de Anestesiologia e Terapia Intensiva Cirúrgica do Instituto do Coração (InCor), HCFMUSP
IVProfessora Associada da Disciplina de Anestesiologia da Faculdade de Medicina da Universidade de São Paulo. Especialista em Terapia Intensiva, AMIB. Médica Supervisora do Serviço de Anestesiologia e Terapia Intensiva Cirúrgica do Instituto do Coração (InCor), HCFMUSP
BACKGROUND AND OBJECTIVES: Myocardial
protection defines the set of strategies aiming at attenuating the intensity
of myocardial ischemia-reperfusion injury during heart surgery and its harmful
consequences on myocardial function. A better understanding of pathophysiological
phenomena related to ischemia-reperfusion events and of the anesthetic-induced
heart protection has given to the anesthesiologist a major role in intraoperative
myocardial protection. The objective of this update was to review the mechanisms
of ischemia-reperfusion-induced myocardial injury and myocardial protection
modalities focusing on anesthetic techniques.
CONTENTS: Ischemia-reperfusion-induced myocardial injury mechanisms and their clinical consequences on heart as well as myocardial protection techniques used during heart surgery are addressed in this review. Special emphasis is given to the role of anesthetic drugs and techniques such as inhaled halogenate anesthetics, opioids and adjuvant anesthetic drugs, since they have been shown to have heart protecting effects during cardiac surgery.
CONCLUSIONS: The association of adequate anesthetic technique using heart protecting agents to usual myocardial protection modalities performed by the surgeon may contribute to the prevention of cardiac surgery-induced myocardial dysfunction and improve postoperative outcome.
Key Words: ANALGESICS, Opioid; ANESTHETICS, Volatile; COMPLICATIONS, Cardiovascular: ischemia-reperfusion; SURGERY, Cardiac
JUSTIFICATIVA Y OBJETIVOS: La protección
miocárdica define el conjunto de estrategias que tienen por objetivo atenuar
la intensidad de la lesión de isquemia-reperfusión miocárdica
durante la cirugía cardiaca y sus consecuencias sobre la función miocárdica.
Un mejor entendimiento de los fenómenos fisiopatológicos relacionados
a la isquemia-reperfusión miocárdica y de la cardioprotección
promovida por determinados fármacos y técnicas anestésicas ha
dado al anestesiologista papel importante en la protección miocárdica
durante el procedimiento quirúrgico. El objetivo de esta revisión
fue abordar los mecanismos de la lesión miocárdica y las modalidades
de protección miocárdica con enfoque para la técnica anestésica.
CONTENIDO: Son abordados los mecanismos de lesión miocárdica durante los eventos de isquemia-reperfusión y sus consecuencias clínicas así como las técnicas de protección realizadas durante la cirugía cardiaca. Énfasis especial fue dada a los fármacos y técnicas anestésicas, como anestésicos halogenados, opioides y fármacos adyuvantes, pues éstos han mostrado efectos cardioprotectores en cirugía cardiaca.
CONCLUSIONES: La asociación de la técnica anestésica adecuada con agentes anestésicos cardioprotectores a las técnicas habituales de protección miocárdica realizadas por el cirujano puede aportar para la prevención de disfunción miocárdica y promover mejor recuperación en el período pos-operatorio.
Myocardial protection during cardiac surgery is defined as the set of strategies aiming at decreasing myocardial oxygen consumption adapting it to the momentary tissue supply and/or at making cardiac cells more resistant to ischemic episodes. The goal is to attenuate the magnitude of ischemia-reperfusion-induced injuries and their noxious early and late consequences, such as acute myocardial infarction (AMI), arrhythmias, ventricular dysfunction, cardiogenic shock and increased perioperative mortality.
The importance of limiting ischemia-reperfusion injuries has been discussed for more than three decades. Maroko et al., in 1971, have proposed that the extension and severity of tissue injury alter coronary occlusion were not determined at ischemia onset, but rather they could be changed by therapeutic manipulations during ischemia 1. Since then, a large number of experimental studies have investigated ischemic mechanisms and myocardial protection modalities. However, few therapeutic interventions have shown to be clinically effective.
Notwithstanding progresses in understanding what determines coronary blood flow, of the relationships between oxygen supply and demand and of cell mechanisms triggered by ischemia, there is still a high incidence of perioperative AMI, which varies from 3% to 30%, depending on the study 2.
Among myocardial protection modalities used during cardiac surgeries, drugs and anesthetic techniques improving tolerance to ischemia and contributing to protect myocardial function are becoming increasingly important for the clinical practice and may influence better postoperative outcomes.
The objective of this review was to address injury mechanisms and myocardial protection modalities with special emphasis to anesthetic techniques able to promote heart protection.
ISCHEMIA AND REPERFUSION INJURY
Myocardial ischemia triggers a series of cell events which start mildly and become progressive noxious with time. Although reperfusion is the final stage of the ischemic process and is essential to restore normal functions and cell survival, this may paradoxically amplify the damage secondary to ischemia. Clinically, it is impossible to separate one process from the other and since ischemia is often followed by reperfusion, cell injuries are indistinctly called ischemia-reperfusion injuries.
During ischemia, regional oxygen supply is beneath metabolic needs, resulting in depletion of adenosine triphosphate (ATP) cell reserves. There is decreased efficiency of ATP-dependent sodium (Na+) and potassium (K+) pumps with increased levels of intracellular sodium. Intracellular ionic hydrogen (H+) is built up as result of decreased excretion of metabolic residues, NADH2 mitochondrial oxidation inhibition and ATP break down. Intracellular H+ build up promotes increased H+ for Na+ exchange in an attempt to maintain cell pH, increasing intracellular Na+ levels and promoting increased intracellular calcium (Ca2+) levels due to the exchange of Na+ for calcium 3,4.
Using intracellular calcium measurement techniques, Marban et al. have found increased intracellular calcium concentrations during ischemia and early reperfusion 5. High intracellular Ca2+ levels activate protein kinases with degradation of proteins and phospholipids 3,6 and decreased maximum calcium-dependent microfilament strength 7. The production of neutrophils and mitochondria-derived free radicals also contributes for proteins and phospholipids degradation 6, which are major constituents of cells and enzymes structure after ischemia is installed.
The post-ischemia injury seems to be amplified when coronary vessels are damaged. Edematous endothelial cells decrease gas exchange efficacy. Vascular smooth and endothelial muscles cells with abnormal function are unable to promote vasodilation and to match regional blood flow to momentary needs. Neutrophils play a central role in spreading cell injury. These cells are attracted by dysfunctional endothelial cells and migrate to the extravascular space releasing free radicals, cytokines and pro-inflammatory substances, with worsening of the endothelial, smooth muscles and myocytes injury 8. There is also neutrophils and platelets aggregation with microvascular obstruction, contributing to supply/demand relationship mismatching 6. One way to activate and scavenger neutrophils is their interaction with ICAM-1, L-selectine and CD11b/CD18 adhesion molecules, the expression of which is induced by ischemia-reperfusion injury 8.
During reperfusion, H+ is rapidly decreased reaching normal levels, and intracellular Na+ is exchanged for extracellular Ca2+ to balance transmembrane electrochemical potentials, increasing intracellular calcium overload 3,4. Recent evidences suggest that intracellular calcium overload may activate selective proteolytic enzymes, the calpains, resulting in selective myofibrils proteolysis, and the time needed for damaged proteins synthesis would explain the time needed for myocardial function recovery after ischemia-reperfusion 9,10. In association with high intracellular calcium levels, there is major increase in oxygen free radicals due to reperfusion with oxygenated blood. Free radicals such as superoxide (O2), hydroxyl (OH-) and hydrogen peroxide (H2O2) are extremely reactive and indistinctly damage all cell components, increasing ischemia-induced cell injuries. Clinical consequences may go from reversible myocardial dysfunction persisting after reperfusion and known as myocardial stunning, to myocardial infarction 3,11,12.
ISCHEMIA-REPERFUSION INJURY AND PERIOPERATIVE MYOCARDIAL COMPLICATIONS
Since the 1960s, the development of perioperative micro-infarctions related to cardiac surgery is admitted as a problem, which may lead to low cardiac, output syndrome and death 13. Some risk factors identified in patients submitted to coronary artery bypass (CAB) procedures, such as coronary disease severity, presence of collateral circulation, previous CAB, recent AMI, emergency procedure, aortic clamping beyond 100 minutes and inadequate myocardial protection, were directly related to perioperative AMI 2,14.
Perioperative AMI may be due to increased oxygen consumption at anesthetic induction or during postoperative recovery 15. However, myocardial ischemia is more likely to develop during the surgical procedure itself. Ischemia during CPB is not solely related to coronary failure severity, but also to the type of myocardial protection, the cardioplegic solution infusion interval and the presence of myocardial hypertrophy. In patients submitted to valve procedures with no evidences of coronary failure, there may be significant CKMB increase in up to 40% of cases without significant manipulation of myocardial muscles 16.
In spite of current perioperative myocardial protection techniques, up to 50% of patients submitted to CAB may release enzymes 17, and mortality is related to the intensity of enzyme release 18. Attempting to prevent undesirable CPB effects, CAB without CPB has been adopted as a feasible alternative to traditional surgery. During CAB without CPB, due to temporary coronary flow occlusion during anastomosis, ischemic preconditioning is the myocardial protection technique of choice.
However, even if the surgery is performed with a beating heart, perioperative AMI may develop in the grafted territory due to poor myocardial tolerance to ischemia, or in non-grafted regions. Although elderly patients submitted to coronary artery bypass, especially in re-operations, and with poor ventricular function, are major candidates to perioperative myocardial ischemia, this may be observed in all age brackets and different types of cardiac procedures.
MYOCARDIAL PROTECTION TECHNIQUES
Most widely used myocardial protection technique during coronary artery bypass is the infusion of hypothermic cardioplegic blood or crystalloid solution, being used in 84.3% of procedures with CPB, according to Karthik et al. 19. Early reports on cardioplegia date from the 1950s, describing electrochemical cardiac arrest in diastole induced by potassium citrate solutions 20, allowing cardiac surgery on standstill and flaccid heart.
However, this solution was associated to high incidence of myocardial necrosis 21. Cardioplegic solutions rich in potassium were abandoned in the mid 1970s, when it has been detected that myocardial necrosis was related to its high concentration and hypertonicity 22. Until the 1980s, hypothermal cardioplegic crystalloid solutions were the major myocardial protection technique during cardiac surgeries. As from the 1980s, studies have shown that cardioplegic blood solutions with potassium would promote more effective myocardial protection as compared to crystalloid solutions, fact observed by decrease in CK-MB release and in the incidence of perioperative infarction 23. Since then, blood cardioplegia has been the milestone of myocardial protection with defined role in intraoperative heart protection 24.
Most widely used cardioplegia administration technique is the intermittent anterograde infusion in the aorta, proximally to the heart, after aortic clamping, or direct infusion in coronary arteries sinus, especially in the presence of associated aortic valve disease. It has been recently proposed the infusion of retrograde cardioplegia in the coronary sinus ostium. This technique assumes the possibility of maintaining uninterrupted infusion and the distribution of cardioplegia to regions irrigated by stenotic coronary vessels, improving sub-endocardial protection 25. The CABG Patch Trial multicentric study has shown that the combination of intermittent anterograde and continuous retrograde cardioplegia would decrease the rate of postoperative cardiac complications as compared to both methods used alone in coronary patients with high surgical risk 26.
The optimal cardioplegic solution temperature is still controversial. Solutions below 15 ºC seem to be more effective in decreasing myocardial oxygen consumption, production of lactates and cell hypoxia markers, as compared to solutions at room temperature. However, solutions around 27 ºC seem to be related to better left ventricular function recovery in the immediate postoperative period 27, in addition to lower incidence of arrhythmias, lower need for defibrillation and less bleeding 28. Another controversial issue is the time interval between cardioplegic infusions, being 20 to 25 minutes the mean period adopted by surgeons. There is also no consensus on the optimal cardioplegic dose, as well as on the addition of substrates, such as I-arginine, anti-arrhythmics or beta-adrenergic antagonists 29,30.
Therapeutic hypothermia is a different strategy to decrease myocardial injury secondary to ischemia during cardiac surgery with cardiopulmonary bypass. The mechanism of this myocardial protection is still not totally explained. Classic explanation is decreased oxygen consumption induced by decreased metabolic cell activity and enzyme reactions, which could limit ischemic zones in risky myocardial regions. In humans cooled to 32 ºC, total oxygen consumption is decreased in 45% and is unrelated to changes in arterial oxygen saturation 31. The increased affinity of oxygen by hemoglobin is compensated by increased blood solubility, maintaining coupled oxygen supply and demand. As temperature decreases, myocardial oxygen consumption also decreases, being below 1% at 12 ºC 32. This heart protective effect is independent of hypothermia-induced bradycardia because it persists after heart rate normalization with a pacemaker 33-35.
Decreased metabolic activity, however, does not seem to be the sole mechanism related to hypothermia-induced heart protection. Decreased lipidic peroxidase and free radicals production were described in a hypothermia model. Globus et al. have shown that post-ischemic and post-traumatic hypothermia decreases extracellular levels of 2,3-dihydrobenzoic acid, which is an indicator of free radicals production 36. In ischemia models after neuro-trauma, mild hypothermia has induced major increase in anti-apoptotic Bsl 2 protein, which may attenuate the onset of cell apoptosis 37. In animal models and in isolated hearts it has been shown that hypothermia preserves cell ATP reserves during ischemia. It has also been shown in acute myocardial infarction animal models that heart protective effects of hypothermia included decrease in infarction size, preservation of microvascular flow and maintenance of cardiac output 38,39.
Hypothermia intensity and duration are determined according to the surgical procedure. Notwithstanding beneficial hypothermia effects on organs protection, increased hypothermia time seems to have paradoxical effects, worsening myocardial injury induced by ischemia-reperfusion. Deep hypothermia for very long periods may exacerbate intracellular calcium overload and induce the formation of peroxides and oxygen reactive species 40,41. Other undesirable hypothermia side effects in patients submitted to heart surgery are electrolytic disorders, increased systemic vascular resistance, tachycardia, decreased metabolism and drugs clearance, coagulation disorders and immune suppression 42-44.
Ischemic preconditioning is an endogenous adaptative and protective response against prolonged myocardial ischemia. This concept was proposed as from early observations by Murry et al., who have observed up to 75% decrease in infarction size after 40-minute occlusion of the left circumflex artery in animal model, when previous minor 5-minute occlusions of this same artery were performed 45,46. This fact was also observed in a series of models, going from isolated cardiomyocytes to in situ hearts, in different animal species 47-49. Although being initially used to decrease infarction incidence and size, it has been observed that this myocardial protection modality could also decrease the incidence of post-ischemic reversible myocardial dysfunction 50 and coronary circulation dysfunction 47.
Different membrane receptors seem to be involved in the ischemic preconditioning phenomenon, including b receptors, opioid and adenosine receptors 51-54. The mechanisms by which ischemic preconditioning triggers the sequence of intracellular events which promotes myocardial protection against repeated ischemic injuries are still subject to massive investigation and are discussed under the section ''preconditioning induced by halogenate inhalational anesthetics''.
Ischemic preconditioning assumes temporary blood flow arrest, may be protective in the presence of several ischemic injuries and play a beneficial role during cardiac procedures. Ghosh and Galinanes have investigated the effects of ischemic preconditioning during procedures with and without CPB. Ischemic preconditioning was achieved by aortic clamping for five minutes followed by 5 minutes reperfusion before the procedure. In patients submitted to CAB without CPB, ischemic preconditioning has promoted less postoperative troponin release 55. This heart protective technique may be used in CAB without CPB and in CAB with CPB 19.
Preconditioning Induced by Halogenate Inhalational Anesthetics
Studies during the 1970s have shown strong evidences that volatile inhalational anesthetics protect myocardium against reversible and irreversible ischemic injuries. Bland et al. have shown that halothane decreased ST segment elevation in a canine model of short-duration occlusion of coronary arteries 56. This same group has also observed decreased infarction size in dogs when halothane was administered before coronary occlusion 57.
Warltier et al. have observed that dogs previously treated with 2% halothane or isoflurane would totally recover myocardial contractile function within 3 to 5 hours after myocardial ischemia, while there was only 50% contractility recovery 5 hours later in the control group 58. The same results were observed in different animal species 59,60. Heart protection has also been observed during cardioplegia-induced cardiac arrest and reperfusion in animal models under inhalational anesthetics 61,62. Mechanisms by which these drugs promote heart protection are not totally known and are issues under massive investigation, however they seem to mimic heart protection by ischemic preconditioning, being defined as anesthetic-induced preconditioning.
Halogenate agents decrease blood pressure, depress myocardial contractility, produce coronary vasodilation, delay electric stimulation conduction and attenuate sympathetic nervous system activity, which contributes to decreased myocardial oxygen consumption. However, other mechanisms different from matching oxygen supply and demand seem to be related to heart protection promoted by halogenate agents. Preservation of high-energy phosphates is one suggested hypothesis.
Freedman et al. have observed higher creatinine-phosphate and ATP concentrations in isolated heart model treated with enflurane before ischemia-reperfusion, as compared to control group 63. Similar results were observed with halothane and other halogenates agents 64. A different mechanism suggested to explain heart protection induced by halogenate agents is the modulation of cell calcium inflow. Some investigators have experimentally shown that halothane, isoflurane and enflurane decreased total cell calcium flow in rats 65 and Guinea pigs 66,67, and canine ventricular myocytes 68.
Eskinder et al. has observed that inhalational anesthetics promote decrease in peak electric potentials induced by calcium inflow through calcium channels type L and T in Purkinje fibers in isolated canine cells 69. The same authors have suggested that these calcium channels located in the sarcoplasmic reticulum, are the major action sites for these anesthetics to modulate calcium inflow. Other proposed mechanisms to decrease cell calcium inflow induced by inhalational anesthetics are the inhibition of sodium-calcium pump 70 and increase in calcium channels expression in the membrane induced by ischemia-reperfusion 61.
The opening of ATP-dependent potassium channels, decreasing action potential duration and attenuating membrane depolarization, could result in lower intracellular calcium levels during ischemic preconditioning and acute myocardial infarction 71 and seems to be involved in heart protection induced by halogenate agents. ATP-dependent potassium channels inhibition by glibenclamide, specific blocker of these channels, was able to eliminate ATP conservation induced by isoflurane in dogs 72. It has also been observed that the maintenance of myocardial contractility after ischemia in dogs inhaling isoflurane was partially inhibited by glibenclamide 73.
There is no consensus on which halogenate agent or inhaled concentration should be used to promote heart protection during cardiac procedures. Some authors have suggested that concentrations close to 1 MAC of different halogenate agents produce similar effects in terms of magnitude of myocardial protection 74. However, some studies have reported significant differences in myocardial protection intensity and in the action mechanisms of different halogenate agents 75-78. To date, halogenate agents have shown consistent myocardial protection effects in animal models of ischemia-reperfusion, however there is no consensus on the agent and dose to be used during cardiac procedures.
Experimental animal studies have shown protection against ischemia-reperfusion by opioid receptors. The contribution of endogenous opioids to body adaptation to hypoxia was firstly reported by Mayfield et al., who have observed that D-Pen2-D-Pen5-Encephaline, sigma receptors agonist, would increase tolerance and survival in mice submitted to severe hypoxia 79,80. It has also been observed that sigma receptor agonist D-Ala2-D-Leu5-Encephaline, trigger for the hibernation of large animals, would induce protective effects in multiple preparations of organs, including isolated hearts for transplant 81.
Schultz et al., in 1996, have show that 300 µg.kg-1 morphine 30 minutes before anterior interventricular artery occlusion would decrease infarction zone from 54% to 12% in rats 82. This morphine-induced decrease was also observed in isolated heart models, in situ hearts and cardiomyocytes 83-85. Improved ventricular contractility after ischemia has also been observed with morphine and fentanyl 86.
The involvement of opioid receptors in ischemic preconditioning, especially sigma receptors, has been observed in several animal species and in humans 51,74,84,85,87. Schultz et al., in 1995, have shown that naloxone would block opioid heart protective effects in rats submitted to ischemic preconditioning, however with no effect in animals not submitted to preconditioning 88. In addition to participating in the triggering of the cascade of ischemic events, opioids seem also to mediate its memory phase in some animal species 89.
Heart protection induced by opioids seems to be modulated by the activation of cardiac receptors, regardless of the action of these drugs on central nervous system. Chien et al. have observed that a naloxone-derived quaternary opioid receptor antagonist, which does not cross blood-brain barrier, was able to totally block protective effects of ischemic preconditioning in isolated heart of rabbits 90. The mechanism by which opioids promote myocardial protection is still under investigation. It has been proposed that opioid-induced heart protection would be result of the activation of ATP-dependent potassium channels, possibly in the mitochondrial membrane 85-87,91. However, intracellular pathways which transduce sigma receptors stimulation effects to final effectors responsible for myocardial protection are not clear. Other opioid-induced intracellular heart protection pathways seem to be related to the activation of inhibitory G 92 protein and C1 proteinokinase 84,91,93.
Other Anesthetic Agents
Some studies have suggested that propofol might attenuate mechanical myocardial dysfunction after ischemia, infarction size and histological changes 94-97. Due to its chemical structure similar to free radical kelating phenolic derived, such as vitamin E, propofol decreases free radicals concentration and their noxious effects 98. Other authors have described that propofol decreases cell ionic calcium inflow and attenuate neutrophils activity, intervening during critical phases of myocardial reperfusion 99,100.
It seems that propofol provides some level of myocardial protection when given during reperfusion in experimental models of isolated heart of rats 101. However, propofol protective effect seems to be momentary, not being considered preconditioning or myocardial protection induced. The administration of blockers of intracellular transduction pathway related to ischemic preconditioning, such as glibenclamide, does not inhibit momentary propofol protective effects 101. De Hert et al. have compared contractile myocardial function and myocardial injury markers in patients submitted to coronary artery bypass with CPB and anesthetized with propofol or sevoflurane and have observed that sevoflurane, but not propofol, was able to preserve postoperative myocardial function, with evidences of decreased myocardial injury after coronary artery bypass surgery 102.
Xenon, an inhalational anesthetic drug experimentally used, has been implied in reversible myocardial dysfunction recovery in ischemia-reperfusion animal model. Animals treated with xenon have evolved with total recovery of ventricular wall thickening fraction, which is a myocardial contractility index, in up to 12 hours after surgery, as compared to the control group where thickening fraction was only back to pre-ischemic levels 48 hours after. Still in the group treated with xenon, there has been attenuation of post-ischemic catecholamine release as compared to control group, which could have contributed to decrease post-ischemia oxygen consumption 103. However, there are no evidences of the clinical use of xenon for myocardial protection in humans.
Notwithstanding the well established role of ketamine as anesthetic agent for congenital heart surgery in patients evolving with circulatory shock, this drug seems to block ischemic preconditioning 104,105 and to intensify myocardial injury. Ketamine decreases 1, 4, 5 triphosphate inositol production 106 and inhibits ATP-dependent potassium channels in the sarcoplasmic membrane 107. Barbiturates have also been classified as possible inhibitors of myocardial protection induced by ischemic preconditioning 108.
Different drugs have been investigated for direct administration in cardioplegic solution or for systemic administration before CPB. Beta-adrenergic antagonists are among drugs knowingly decreasing AMI injury, by decreasing myocardial oxygen consumption and sympathetic tone, and by stabilizing cell membranes 109. Beta-adrenergic antagonists in the early hours after AMI were clearly beneficial in decreasing mortality and AMI-related complications. Hours preceding surgery, the anesthetic-surgical procedure per se and CPB trigger massive adrenergic stimulation 110. Since myocardial infarction during cardiac surgery may be related to perioperative tachycardia and ischemia, beta-adrenergic antagonists are particularly interesting 111, and may be used preventively before intervention or therapeutically during surgery 112.
The maintenance of beta-adrenergic antagonists until the day of the coronary artery bypass surgery was controversial 113,114 and clinical research has brought arguments favoring this practice as of 1979. Similarly to non-cardiac surgeries, beta-adrenergic antagonists should be maintained until the day of the surgery 115. Ponten et al. 116 have shown in a randomized study that metroprolol withdrawal 60 hours before surgery was followed by preoperative AMI and perioperative tachycardia and ischemia. Similar results were observed by Chung et al. 117. Studies by du Cailar et al. 118 and Rao et al. 119 have shown that preoperative propranolol has significantly lowered creatinophosphokinase MB fraction increase.
Oral 80 mg sotalol every 12 hours starting two hours before surgery has promoted 43% decrease in the incidence of postoperative supraventricular arrhythmias 120. Podesser et al. have shown that continuous intraoperative nifedipine infusion associated to 12 µg.kg-1.h-1 metroprolol, after CPB for 24 hours, has decreased the incidence of ischemia and supraventricular tachycardia 121.
Slogoff et al. 122 have compared, in a prospective non-randomized study, the incidence of ischemia in patients submitted to coronary artery bypass. Individuals treated with beta-adrenergic antagonists until the intervention presented less tachycardia or myocardial ischemia as compared to those receiving diltiazem or nifedipine. For the latter, the number of ischemic episodes was similar to patients not receiving beta-adrenergic antagonists or calcium channel blockers. The reason for the difference between beta-adrenergic antagonists and calcium channel blockers is still unknown 112.
However Kyosola et al. 123 have described a network of intra-axonal catecholamines in the right atrium of 16 out of 65 patients during cardiac surgery, and have shown that its presence is related to severe complications, such as arrhythmias lasting up to 2 weeks after surgery, myocardial infarction and death. According to Piriou et al., continuing the treatment with beta-adrenergic antagonists could have prevented these complications 112.
Although beta-adrenergic antagonists were effective in decreasing perioperative events in high-risk patients submitted to non cardiac surgery and to vascular surgery, no randomized study has yet evaluated whether this therapy is beneficial when used in the preoperative period of coronary artery bypass procedures 124. A therapeutic trial involving 60 patients submitted to CAB with CPB has shown that esmolol, beta-adrenergic antagonist with ultra-short action, used to decrease myocardial contractility during continuous normothermal coronary perfusion promotes myocardial protection comparable to blood or crystalloid cardioplegia 125.
As to a2 receptor agonists, perioperative clonidine is effective in decreasing morbidity/mortality in patients submitted to non-cardiac surgeries 126. There are no evidences of heart protecting effects of a2-adrenergic agonists and further studies are needed to define the precise indication of such drugs for patients submitted to cardiac surgery. Loick et al. have observed that clonidine was less effective than high thoracic epidural anesthesia in decreasing perioperative stress via sympatholysis and troponin release in patients submitted to coronary artery bypass 127.
Experimental studies and small clinical trials have shown encouraging results of myocardial performance improvement in patients submitted to cardiac surgery with the infusion of glucose-insulin-potassium (GIK) solution 128-130. The mechanism by which GIK solution promotes heart protection seems to be related to ATP-dependent potassium channel activity recovery since glucose decreases the activity of such channels 129.
Zhang et al. have observed that insulin infusion decreases apoptosis induced by ischemia and reperfusion 131. However, notwithstanding the beneficial effect experimentally observed in small series, one study was unable to show the benefits of GIK in high-risk patients submitted to coronary artery bypass with CPB 132. The same result was observed in patients submitted to CAB without CPB 130. On the other hand, strict control of perioperative glycemia both in diabetes and non-diabetes patients, may play a critical role in decreasing morbidity and mortality during this period 133.
Some authors have shown in experimental models that adenosine activates proteinokinase C metabolic pathway, supposedly involved with myocardial protection induced by ischemic preconditioning. However, clinical trials with adenosine have not shown the expected benefits as compared to results obtained by experimental studies 29,134.
Thoracic Epidural Anesthesia
Thoracic epidural anesthesia with local anesthetics has been used to promote perioperative analgesia and decrease myocardial oxygen consumption by blocking T1 to T5 thoracic sympathetic fiber roots, which supply sympathetic innervation to the heart. Heart protection provided by thoracic epidural anesthesia is related to improved myocardial oxygen balance induced by sympathetic block, which decreases myocardial oxygen consumption secondary to bradycardia, decreases cardiac output and systemic vascular resistance, and improves regional perfusion with dilatation of post stenotic segments of partially obstructed arteries.
Studies have shown that thoracic epidural anesthesia may attenuate endocrine-metabolic response secondary to surgery, with decrease in catecholamine release and serum levels, which contributes to decrease oxygen consumption 135. This improvement in myocardial oxygen balance is clinically observed by improved angina in coronary artery disease patients 136. Due to the efficiency of thoracic epidural analgesia, it is possible to decrease the doses of systemic opioids thus decreasing tracheal intubation time and pulmonary diseases in the postoperative period of cardiac surgeries 137-139.
However, in spite of beneficial effects of thoracic epidural anesthesia on myocardial oxygen balance, no direct myocardial mechanism to increase tolerance to ischemia and reperfusion has been described. In a recent meta analysis with 15 trials and 1178 patients, thoracic epidural anesthesia for coronary artery bypass was not effective in decreasing mortality (0.7% versus 0.3% general anesthesia) or the incidence of myocardial infarction (2.3% versus 3.4% general anesthesia). On the other hand, there has been significant decrease in arrhythmias (OR 0.52), pulmonary complications (OR 0.41) and tracheal intubation time (4.5 hours). Spinal analgesia with opioids has had no effects on mortality, incidence of infarction, arrhythmias, mortality and tracheal intubation time as compared to general anesthesia 140.
To date, most widely used heart protection modalities during cardiac surgery with CPB are cardioplegic solutions infusion in their different modalities, and regional and systemic hypothermia, which effectively decrease myocardial oxygen consumption and preserve myocardial contractility. In patients submitted to CAB without CPB, ischemic preconditioning has a well-established role, being even used in patients submitted to cardiac surgery with CPB. Some substances, such as systemic or regional beta-adrenergic antagonists have shown to protect myocardial function sometimes similarly to the protection given by cardioplegic solutions. Regional anesthetic techniques, considered protective, play no confirmed role on heart protection. On the other hand, inhalational anesthetics and opioids play important roles in heart protection. The association of myocardial protection techniques implemented by surgical and anesthetic teams may have synergistic effects, contributing to better myocardial function preservation and postoperative evolution in cardiac surgery.
01. Maroko PR, Kjekshus JK, Sobel BE et al - Factors influencing infarct size following experimental coronary artery occlusions. Circulation, 1971;43:67-82. [ Links ]
02. Kloner RA, Rezkalla SH - Cardiac protection during acute myocardial infarction: where do we stand in 2004? J Am Coll Cardiol, 2004;44:276-286. [ Links ]
03. Opie LH - Myocardial Reperfusion: New Ischemic Syndromes em: Opie LH - The Heart. Physiology, from Cell to Circulation. 3rd Ed, Philadelphia, Lippincott-Raven, 1998;563-588. [ Links ]
04. Opie LH - Oxygen Lack: Ischemia and Angina em: Opie LH - The Heart. Physiology, from Cell to Circulation. 3rd Ed, Philadelphia, Lippincott-Raven, 1998;515-541. [ Links ]
05. Marban E, Koretsune Y, Corretti M et al - Calcium and its role in myocardial cell injury during ischemia and reperfusion. Circulation, 1989;80:(Suppl6):IV17-22. [ Links ]
06. Maxwell SR, Lip GY - Reperfusion injury: a review of the pathophysiology, clinical manifestations and therapeutic options. Int J Cardiol, 1997;58:95-117. [ Links ]
07. Bolli R - Mechanism of myocardial "stunning". Circulation, 1990;82:723-738. [ Links ]
08. Jordan JE, Zhao ZQ, Vinten-Johansen J - The role of neutrophils in myocardial ischemia-reperfusion injury. Cardiovasc Res, 1999;43:860-878. [ Links ]
09. Perrin C, Ecarnot-Laubriet A, Vergely C et al - Calpain and caspase-3 inhibitors reduce infarct size and post-ischemic apoptosis in rat heart without modifying contractile recovery. Cell Mol Biol, 2003;49:497-505. [ Links ]
10. Friedrich P - The intriguing Ca2+ requirement of calpain activation. Biochem Biophys Res Commun, 2004;323:1131-1133. [ Links ]
11. Bolli R, Marban E - Molecular and cellular mechanisms of myocardial stunning. Physiol Rev, 1999;79:609-634. [ Links ]
12. Braunwald E, Kloner RA - The stunned myocardium: prolonged, postischemic ventricular dysfunction. Circulation, 1982;66: 1146-1149. [ Links ]
13. Morales AR, Fine G, Taber RE - Cardiac surgery and myocardial necrosis. Arch Pathol, 1967;83:71-79. [ Links ]
14. Greaves SC, Rutherford JD, Aranki SF et al - Current incidence and determinants of perioperative myocardial infarction in coronary artery surgery. Am Heart J, 1996;132:572-578. [ Links ]
15. Lell WA, Walker DR, Blackstone EH et al - Evaluation of myocardial damage in patients undergoing coronary-artery bypass procedures with halothane-N2O anesthesia and ajuvants. Anesth Analg, 1977;56:556-563. [ Links ]
16. Hultgren HN, Miyagawa M, Buch W et al - Ischemic myocardial injury during cardiopulmonary bypass surgery. Am Heart J, 1973;85:167-176. [ Links ]
17. Costa MA, Carere RG, Lichtenstein SV et al - Incidence, predictors, and significance of abnormal cardiac enzyme rise in patients treated with bypass surgery in the arterial revascularization therapies study (ARTS). Circulation, 2001; 104:2689-2693. [ Links ]
18. Mentzer RM Jr - Does size matter? What is your infarct rate after coronary artery bypass grafting? J Thorac Cardiovasc Surg, 2003;126:326-328. [ Links ]
19. Karthik S, Grayson AD, Oo AY et al - A survey of current myocardial protection practices during coronary artery bypass grafting. Ann R Coll Surg Engl, 2004;86:413-415. [ Links ]
20. Melrose DG, Dreyer B, Bentall HH et al - Elective cardiac arrest. Lancet, 1955;269:21-22. [ Links ]
21. Helmsworth JA, Kaplan S, Clark LC Jr et al - Myocardial injury associated with a systole induced with potassium citrate. Ann Surg, 1959;149:200-206. [ Links ]
22. Tyers GF, Todd GJ, Niebauer IM et al - The mechanism of myocardial damage following potassium citrate (Melrose) cardioplegia. Surgery, 1975;78:45-53. [ Links ]
23. Fremes SE, Christakis GT, Weisel RD et al - A clinical trial of blood and crystalloid cardioplegia. J Thorac Cardiovasc Surg, 1984;88:726-741. [ Links ]
24. Robinson LA, Schwarz GD, Goddard DB et al - Myocardial protection for acquired heart disease surgery: results of a national survey. Ann Thorac Surg, 1995;59:361-372. [ Links ]
25. Nicolini F, Beghi C, Muscari C et al - Myocardial protection in adult cardiac surgery: current options and future challenges. Eur J Cardiothorac Surg, 2003;24:986-993. [ Links ]
26. Flack JE 3rd, Cook JR, May SJ et al - Does cardioplegia type affect outcome and survival in patients with advanced left ventricular dysfunction? Results from the CABG Patch Trial. Circulation, 2000;102(Supp19):III84-III89. [ Links ]
27. Hayashida N, Ikonomidis JS, Weisel RD et al - Adequate distribution of warm cardioplegic solution. J Thorac Cardiovasc Surg, 1995;110:800-812. [ Links ]
28. Fromes Y, Fischer M, Duffet T - Cardioplégie tiède antérograde intermittente: vers une simplification de la protecion myoquardique en chirurgie coronariene. J Chirurgie Thorac Cardiovasc, 1997;3:11-16. [ Links ]
29. Rinne T, Harmoinen A, Kaukinen S - Esmolol cardioplegia in unstable coronary revascularisation patients. A randomised clinical trial. Acta Anaesthesiol Scand, 2000;44:727-732. [ Links ]
30. Vinten-Johansen J, Zhao ZQ, Corvera JS et al - Adenosine in myocardial protection in on-pump and off-pump cardiac surgery. Ann Thorac Surg, 2003;75:691-699. [ Links ]
31. Bigelow WG, Callaghan JC, Hopps JA - General hypothermia for experimental intracardiac surgery; the use of electrophrenic respirations, an artificial pacemaker for cardiac standstill and radio-frequency rewarming in general hypothermia. Ann Surg, 1950;132:531-539. [ Links ]
32. Niazi SA, Lewis FJ - Effects of carbon dioxide on ventricular fibrillation and heart block during hypothermia in rats and dogs. S Forum, 1955;5:106-109. [ Links ]
33. Chien GL, Wolff RA, Davis RF et al - "Normothermic range" temperature affects myocardial infarct size. Cardiovasc Res, 1994;28:1014-1017. [ Links ]
34. Birnbaum Y, Hale SL, Kloner RA - Ischemic preconditioning at a distance: reduction of myocardial infarct size by partial reduction of blood supply combined with rapid stimulation of the gastrocnemius muscle in the rabbit. Circulation, 1997;96: 1641-1646. [ Links ]
35. Hale SL, Kloner RA - Myocardial temperature in acute myocardial infarction: protection with mild regional hypothermia. Am J Physiol, 1997;273:220-227. [ Links ]
36. Globus MY, Busto R, Lin B et al - Detection of free radical activity during transient global ischemia and recirculation: effects of intraischemic brain temperature modulation. J Neurochem, 1995;65:1250-1256. [ Links ]
37. Zhang Z, Sobel RA, Cheng D et al - Mild hypothermia increases Bcl-2 protein expression following global cerebral ischemia. Brain Res Mol Brain Res, 2001;95:75-85. [ Links ]
38. Dae MW, Gao DW, Sessler DI et al - Effect of endovascular cooling on myocardial temperature, infarct size, and cardiac output in human-sized pigs. Am J Physiol Heart Circ Physiol, 2002; 282:1584-1591. [ Links ]
39. Dae MW, Gao DW, Ursell PC et al - Safety and efficacy of endovascular cooling and rewarming for induction and reversal of hypothermia in human-sized pigs. Stroke, 2003;34:734-738. [ Links ]
40. Kumar K, Wu X, Evans AT et al - The effect of hypothermia on induction of heat shock protein (HSP)-72 in ischemic brain. Metab Brain Dis, 1995;10:283-291. [ Links ]
41. Labow RS, Hendry PJ, Meek E et al - Temperature affects human cardiac sarcoplasmic reticulum energy-mediated calcium transport. J Mol Cell Cardiol, 1993;25:1161-1170. [ Links ]
42. Valeri CR, Feingold H, Cassidy G et al - Hypothermia-induced reversible platelet dysfunction. Ann Surg, 1987;205:175-181. [ Links ]
43. Valeri CR, MacGregor H, Cassidy G et al - Effects of temperature on bleeding time and clotting time in normal male and female volunteers. Crit Care Med, 1995;23:698-704. [ Links ]
44. Shiozaki T, Hayakata T, Taneda M et al - A multicenter prospective randomized controlled trial of the efficacy of mild hypothermia for severely head injured patients with low intracranial pressure. Mild Hypothermia Study Group in Japan. J Neurosurg, 2001;94:50-54. [ Links ]
45. Murry CE, Jennings RB, Reimer KA - Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation, 1986;74:1124-1136. [ Links ]
46. Reimer KA, Murry CE, Yamasawa I et al - Four brief periods of myocardial ischemia cause no cumulative ATP loss or necrosis. Am J Physiol, 1986;251:1306-1315. [ Links ]
47. Rubino A, Yellon DM - Ischaemic preconditioning of the vasculature: an overlooked phenomenon for protecting the heart? Trends Pharmacol Sci, 2000;21:225-230. [ Links ]
48. Okubo S, Xi L, Bernardo NL et al - Myocardial preconditioning: basic concepts and potential mechanisms. Mol Cell Biochem, 1999;196:3-12. [ Links ]
49. Bernardo NL, D'Angelo M, Okubo S et al - Delayed ischemic preconditioning is mediated by opening of ATP-sensitive potassium channels in the rabbit heart. Am J Physiol, 1999;276:1323-1330. [ Links ]
50. Xuan YT, Tang XL, Banerjee S et al - Nuclear factor-kappa B plays an essential role in the late phase of ischemic preconditioning in conscious rabbits. Circ Res, 1999;84:1095-1109. [ Links ]
51. Schultz JJ, Hsu AK, Gross GJ - Ischemic preconditioning and morphine-induced cardioprotection involve the delta (delta)-opioid receptor in the intact rat heart. J Mol Cell Cardiol, 1997;29:2187-2195. [ Links ]
52. Schultz JJ, Hsu AK, Gross GJ - Ischemic preconditioning is mediated by a peripheral opioid receptor mechanism in the intact rat heart. J Mol Cell Cardiol, 1997;29:1355-1362. [ Links ]
53. Carr CS, Hill RJ, Masamune H et al - Evidence for a role for both the adenosine A1 and A3 receptors in protection of isolated human atrial muscle against simulated ischaemia. Cardiovasc Res, 1997;36:52-59. [ Links ]
54. Cleveland JC Jr, Meldrum DR, Rowland RT et al - Adenosine preconditioning of human myocardium is dependent upon the ATP-sensitive K+ channel. J Mol Cell Cardiol, 1997;29: 175-182. [ Links ]
55. Ghosh S, Galinanes M - Protection of the human heart with ischemic preconditioning during cardiac surgery: role of cardiopulmonary bypass. J Thorac Cardiovasc Surg, 2003;126: 133-142. [ Links ]
56. Bland JH, Lowenstein E - Halothane-induced decrease in experimental myocardial ischemia in the non-failing canine heart. Anesthesiology, 1976;45:287-293. [ Links ]
57. Davis RF, DeBoer LW, Rude RE et al - The effect of halothane anesthesia on myocardial necrosis, hemodynamic performance, and regional myocardial blood flow in dogs following coronary artery occlusion. Anesthesiology, 1983;59:402-411. [ Links ]
58. Warltier DC, al-Wathiqui MH, Kampine JP et al - Recovery of contractile function of stunned myocardium in chronically instrumented dogs is enhanced by halothane or isoflurane. Anesthesiology, 1988;69:552-565. [ Links ]
59. Boutros A, Wang J, Capuano C - Isoflurane and halothane increase adenosine triphosphate preservation, but do not provide additive recovery of function after ischemia, in preconditioned rat hearts. Anesthesiology, 1997;86:109-117. [ Links ]
60. Mattheussen M, Rusy BF, Van Aken H et al - Recovery of function and adenosine triphosphate metabolism following myocardial ischemia induced in the presence of volatile anesthetics. Anesth Analg, 1993;76:69-75. [ Links ]
61. Lochner A, Harper IS, Salie R et al - Halothane protects the isolated rat myocardium against excessive total intracellular calcium and structural damage during ischemia and reperfusion. Anesth Analg, 1994;79:226-233. [ Links ]
62. Preckel B, Thamer V, Schalack W - Beneficial effects of sevoflurane and desflurane against myocardial reperfusion injury after cardioplegic arrest. Can J Anaesth, 1999;40: 1076-1081. [ Links ]
63. Freedman BM, Hamm DP, Everson CT et al - Enflurane enhances postischemic functional recovery in the isolated rat heart. Anesthesiology, 1985;62:29-33. [ Links ]
64. Coetzee A - Comparison of the effects of propofol and halothane on acute myocardial ischaemia and myocardial reperfusion injury. S Afr Med J, 1996;86:(Suppl2):85-90. [ Links ]
65. Ikemoto Y, Yatani A, Arimura H et al - Reduction of the slow inward current of isolated rat ventricular cells by thiamylal and halothane. Acta Anaesthesiol Scand, 1985;29:583-586. [ Links ]
66. Terrar DA, Victory JG - Isoflurane depresses membrane currents associated with contraction in myocytes isolated from guinea-pig ventricle. Anesthesiology, 1988;69:742-749. [ Links ]
67. Terrar DA, Victory JG - Influence of halothane on electrical coupling in cell pairs isolated from guinea-pig ventricle. Br J Pharmacol, 1988;94:509-514. [ Links ]
68. Bosnjak ZJ, Supan FD, Rusch NJ - The effects of halothane, enflurane, and isoflurane on calcium current in isolated canine ventricular cells. Anesthesiology, 1991;74:340-345. [ Links ]
69. Eskinder H, Rusch NJ, Supan FD et al - The effects of volatile anesthetics on L- and T-type calcium channel currents in canine cardiac Purkinje cells. Anesthesiology, 1991;74:919-926. [ Links ]
70. Connelly TJ, Coronado R - Activation of the Ca2+ release channel of cardiac sarcoplasmic reticulum by volatile anesthetics. Anesthesiology, 1994;81:459-469. [ Links ]
71. Cavero I, Djellas Y, Guillon JM - Ischemic myocardial cell protection conferred by the opening of ATP-sensitive potassium channels. Cardiovasc Drugs Ther, 1995;9:(Suppl2):245-255. [ Links ]
72. Nakayama M, Fujita S, Kanaya N et al - Blockade of ATP-sensitive K+ channel abolishes the anti-ischemic effects of isoflurane in dog hearts. Acta Anaesthesiol Scand, 1997;41:531-535. [ Links ]
73. Kersten JR, Lowe D, Hettrick DA et al - Glyburide, a KATP channel antagonist, attenuates the cardioprotective effects of isoflurane in stunned myocardium. Anesth Analg, 1996;83: 27-33. [ Links ]
74. Kato R, Foex P - Myocardial protection by anesthetic agents against ischemia-reperfusion injury: an update for anesthesiologists. Can J Anaesth, 2002;49:777-791. [ Links ]
75. Preckel B, Schlack W, Comfere T et al - Effects of enflurane, isoflurane, sevoflurane and desflurane on reperfusion injury after regional myocardial ischaemia in the rabbit heart in vivo. Br J Anaesth, 1998;81:905-912. [ Links ]
76. Preckel B, Schlack W, Thamer V - Enflurane and isoflurane, but not halothane, protect against myocardial reperfusion injury after cardioplegic arrest with HTK solution in the isolated rat heart. Anesth Analg, 1998;87:1221-1227. [ Links ]
77. Conradie S, Coetzee A, Coetzee J - Anesthetic modulation of myocardial ischemia and reperfusion injury in pigs: comparison between halothane and sevoflurane. Can J Anaesth, 1999;46:71-81. [ Links ]
78. Roscoe AK, Christensen JD, Lynch C 3rd - Isoflurane, but not halothane, induces protection of human myocardium via adenosine A1 receptors and adenosine triphosphate-sensitive potassium channels. Anesthesiology, 2000;92:1692-1701. [ Links ]
79. Mayfield KP, D'Alecy LG - Role of endogenous opioid peptides in the acute adaptation to hypoxia. Brain Res, 1992;582:226-231. [ Links ]
80. Mayfield KP, D'Alecy LG - Delta-1 opioid agonist acutely increases hypoxic tolerance. J Pharmacol Exp Ther, 1994;268: 683-688. [ Links ]
81. Chien S, Oeltgen PR, Diana JN et al - Extension of tissue survival time in multiorgan block preparation with a delta opioid DADLE ( [D-Ala2, D-Leu5 ]-enkephalin). J Thorac Cardiovasc Surg, 1994;107:964-967. [ Links ]
82. Schultz JE, Hsu AK, Gross GJ - Morphine mimics the cardioprotective effect of ischemic preconditioning via a glibenclamide-sensitive mechanism in the rat heart. Circ Res, 1996;78:1100-1104. [ Links ]
83. Takasaki Y, Wolff RA, Chien GL et al - Met5-enkephalin protects isolated adult rabbit cardiomyocytes via delta-opioid receptors. Am J Physiol, 1999;277:2442-2450. [ Links ]
84. Miki T, Cohen MV, Downey JM - Opioid receptor contributes to ischemic preconditioning through protein kinase C activation in rabbits. Mol Cell Biochem, 1998;186:3-12. [ Links ]
85. Liang BT, Gross GJ - Direct preconditioning of cardiac myocytes via opioid receptors and KATP channels. Circ Res, 1999;84: 1396-1400. [ Links ]
86. Kato R, Ross S, Foex P - Fentanyl protects the heart against ischaemic injury via opioid receptors, adenosine A1 receptors and KATP channel linked mechanisms in rats. Br J Anaesth, 2000;84:204-214. [ Links ]
87. Bell SP, Sack MN, Patel A et al - Delta opioid receptor stimulation mimics ischemic preconditioning in human heart muscle. J Am Coll Cardiol, 2000;36:2296-2302. [ Links ]
88. Schultz JE, Rose E, Yao Z et al - Evidence for involvement of opioid receptors in ischemic preconditioning in rat hearts. Am J Physiol, 1995;268:2157-2161. [ Links ]
89. Chien GL, Van Winkle DM - Naloxone blockade of myocardial ischemic preconditioning is stereoselective. J Mol Cell Cardiol, 1996;28:1895-1900. [ Links ]
90. Chien GL, Mohtadi K, Wolff RA et al - Naloxone blockade of myocardial ischemic preconditioning does not require central nervous system participation. Basic Res Cardiol, 1999;94: 136-143. [ Links ]
91. Huh J, Gross GJ, Nagase H et al - Protection of cardiac myocytes via delta(1)-opioid receptors, protein kinase C, and mitochondrial K(ATP) channels. Am J Physiol Heart Circ Physiol, 2001;280:H377-H383. [ Links ]
92. Schultz Je-J, Hsu AK, Nagase H et al - TAN-67, a delta 1-opioid receptor agonist, reduces infarct size via activation of Gi/o proteins and KATP channels. Am J Physiol, 1998;274:H909-H914. [ Links ]
93. Kato R, Foex P - Fentanyl reduces infarction but not stunning via delta-opioid receptors and protein kinase C in rats. Br J Anaesth, 2000;84:608-614. [ Links ]
94. Javadov SA, Lim KH, Kerr PM et al - Protection of hearts from reperfusion injury by propofol is associated with inhibition of the mitochondrial permeability transition. Cardiovasc Res, 2000;45:360-369. [ Links ]
95. Ko SH, Yu CW, Lee SK et al - Propofol attenuates ischemia-reperfusion injury in the isolated rat heart. Anesth Analg, 1997;85:719-724. [ Links ]
96. Kokita N, Hara A, Abiko Y et al - Propofol improves functional and metabolic recovery in ischemic reperfused isolated rat hearts. Anesth Analg, 1998;86:252-258. [ Links ]
97. Yoo KY, Yang SY, Lee J et al - Intracoronary propofol attenuates myocardial but not coronary endothelial dysfunction after brief ischaemia and reperfusion in dogs. Br J Anaesth, 1999;82:90-96. [ Links ]
98. Murphy PG, Myers DS, Davies MJ et al - The antioxidant potential of propofol (2,6-diisopropylphenol). Br J Anaesth, 1992;68:613-618. [ Links ]
99. Nakae Y, Fujita S, Namiki A - Propofol inhibits Ca(2+) transients but not contraction in intact beating guinea pig hearts. Anesth Analg, 2000;90:1286-1292. [ Links ]
100. Galley HF, Dubbels AM, Webster NR - The effect of midazolam and propofol on interleukin-8 from human polymorphonuclear leukocytes. Anesth Analg, 1998;86:1289-1293. [ Links ]
101. Mathur S, Farhangkhgoee P, Karmazyn M - Cardioprotective effects of propofol and sevoflurane in ischemic and reperfused rat hearts: role of K(ATP) channels and interaction with the sodium-hydrogen exchange inhibitor HOE 642 (cariporide). Anesthesiology, 1999;91:1349-1360. [ Links ]
102. De Hert SG, ten Broecke PW, Mertens E et al - Sevoflurane but not propofol preserves myocardial function in coronary surgery patients. Anesthesiology, 2002;97:42-49. [ Links ]
103. Hartlage MA, Berendes E, Van Aken H et al - Xenon improves recovery from myocardial stunning in chronically instrumented dogs. Anesth Analg, 2004;99:655-664. [ Links ]
104. Mullenheim J, Rulands R, Wietschorke T et al - Late preconditioning is blocked by racemic ketamine, but not by S(+)-ketamine. Anesth Analg, 2001;93:265-270. [ Links ]
105. Mullenheim J, Frassdorf J, Preckel B et al - Ketamine, but not S(+)-ketamine, blocks ischemic preconditioning in rabbit hearts in vivo. Anesthesiology, 2001;94:630-636. [ Links ]
106. Kudoh A, Matsuki A - Ketamine inhibits inositol 1,4,5-trisphosphate production depending on the extracellular Ca2+ concentration in neonatal rat cardiomyocytes. Anesth Analg, 1999;89:1417-1422. [ Links ]
107. Ko SH, Lee SK, Han YJ et al - Blockade of myocardial ATP-sensitive potassium channels by ketamine. Anesthesiology, 1997;87:68-74. [ Links ]
108. Tsutsumi Y, Oshita S, Kitahata H et al - Blockade of adenosine triphosphate-sensitive potassium channels by thiamylal in rat ventricular myocytes. Anesthesiology, 2000;92:1154-1159. [ Links ]
109. Khandoudi N, Percevault-Albadine J, Bril A - Comparative effects of carvedilol and metoprolol on cardiac ischemia- reperfusion injury. J Cardiovasc Pharmacol, 1998;32:443-451. [ Links ]
110. Hoar PF, Stone JG, Faltas AN et al - Hemodynamic and adrenergic responses to anesthesia and operation for myocardial revascularization. J Thorac Cardiovasc Surg, 1980;80:242-248. [ Links ]
111. Slogoff S, Keats AS - Does perioperative myocardial ischemia lead to postoperative myocardial infarction? Anesthesiology, 1985;62:107-114. [ Links ]
112. Piriou V, Aouifi A, Lehot JJ - Perioperative beta-blockers. Part two: therapeutic indications. Can J Anaesth, 2000;47:664-672. [ Links ]
113. Viljoen JF, Estafanous FG, Kellner GA - Propranolol and cardiac surgery. J Thorac Cardiovasc Surg, 1972;64:826-830. [ Links ]
114. Faulkner SL, Hopkins JT, Boerth RC et al - Time required for complete recovery from chronic propranolol therapy. N Engl J Med, 1973;289:607-609. [ Links ]
115. Fontaine B, Bertrandias E, Tournay D et al - Anesthesia for aorto-coronary bypass. Ann Anesthesiol Fr, 1979;20:411-419. [ Links ]
116. Ponten J, Haggendal J, Milocco I et al - Long-term metoprolol therapy and neuroleptanesthesia in coronary artery surgery: withdrawal versus maintenance of beta 1-adrenoreceptor blockade. Anesth Analg, 1983;62:380-390. [ Links ]
117. Chung F, Houston PL, Cheng DC et al - Calcium channel blockade does not offer adequate protection from perioperative myocardial ischemia. Anesthesiology, 1988;69:343-347. [ Links ]
118. du Cailar C, Maille JG, Jones W et al - MB creatine kinase and the evaluation of myocardial injury following aortocoronary bypass operation. Ann Thorac Surg, 1980;29:8-14. [ Links ]
119. Rao PS, Brock FE, Cleary K et al - Effect of intraoperative propranolol on serum creatinine kinase MB release in patients having elective cardiac operations. J Thorac Cardiovasc Surg, 1984;88:562-566. [ Links ]
120. Pfisterer ME, Kloter-Weber UC, Huber M et al - Prevention of supraventricular tachyarrhythmias after open heart operation by low-dose sotalol: a prospective, double-blind, randomized, placebo-controlled study. Ann Thorac Surg, 1997;64: 1113-1119. [ Links ]
121. Podesser BK, Schwarzacher S, Zwoelfer W et al - Comparison of perioperative myocardial protection with nifedipine versus nifedipine and metoprolol in patients undergoing elective coronary artery bypass grafting. J Thorac Cardiovasc Surg, 1995;110:1461-1469. [ Links ]
122. Slogoff S, Keats AS - Does chronic treatment with calcium entry blocking drugs reduce perioperative myocardial ischemia? Anesthesiology, 1988;68:676-680. [ Links ]
123. Kyosola K, Mattila T, Harjula A et al - Life-threatening complications of cardiac operations and occurrence of myocardial catecholamine bombs. J Thorac Cardiovasc Surg, 1988;95: 334-339. [ Links ]
124. Ferguson TB Jr, Coombs LP, Peterson ED - Preoperative beta-blocker use and mortality and morbidity following CABG surgery in North America. JAMA, 2002;287:2221-2227. [ Links ]
125. Mehlhorn U, Sauer H, Kuhn-Regnier F et al - Myocardial beta-blockade as an alternative to cardioplegic arrest during coronary artery surgery. Cardiovasc Surg, 1999;7:549-557. [ Links ]
126. Wallace AW, Galindez D, Salahieh A et al - Effect of clonidine on cardiovascular morbidity and mortality after noncardiac surgery. Anesthesiology, 2004;101:284-293. [ Links ]
127. Loick HM, Schmidt C, Van Aken H et al - High thoracic epidural anesthesia, but not clonidine, attenuates the perioperative stress response via sympatholysis and reduces the release of troponin T in patients undergoing coronary artery bypass grafting. Anesth Analg, 1999;88:701-709. [ Links ]
128. Rao V, Merante F, Weisel RD et al - Insulin stimulates pyruvate dehydrogenase and protects human ventricular cardiomyo- cytes from simulated ischemia. J Thorac Cardiovasc Surg, 1998;116:485-494. [ Links ]
129. LaDisa JF Jr, Krolikowski JG, Pagel PS et al - Cardioprotection by glucose-insulin-potassium: dependence on KATP channel opening and blood glucose concentration before ischemia. Am J Physiol Heart Circ Physiol, 2004;287:601-607. [ Links ]
130. Lell WA, Nielsen VG, McGiffin DC et al - Glucose-insulin-potassium infusion for myocardial protection during off-pump coronary artery surgery. Ann Thorac Surg, 2002;73:1246-1251. [ Links ]
131. Zhang HF, Fan Q, Qian XX et al - Role of insulin in the anti-apoptotic effect of glucose-insulin-potassium in rabbits with acute myocardial ischemia and reperfusion. Apoptosis, 2004;9:777-783. [ Links ]
132. Bruemmer-Smith S, Avidan MS, Harris B et al - Glucose, insulin and potassium for heart protection during cardiac surgery. Br J Anaesth, 2002;88:489-495. [ Links ]
133. Gu W, Pagel PS, Warltier DC et al - Modifying cardiovascular risk in diabetes mellitus. Anesthesiology, 2003;98:774-779. [ Links ]
134. Belhomme D, Peynet J, Florens E et al - Is adenosine preconditioning truly cardioprotective in coronary artery bypass surgery? Ann Thorac Surg, 2000;70:590-594. [ Links ]
135. Kirno K, Friberg P, Grzegorczyk A et al - Thoracic epidural anesthesia during coronary artery bypass surgery: effects on cardiac sympathetic activity, myocardial blood flow and metabolism, and central hemodynamics. Anesth Analg, 1994;79:1075-1081. [ Links ]
136. Gramling-Babb PM, Zile MR, Reeves ST - Preliminary report on high thoracic epidural analgesia: relationship between its therapeutic effects and myocardial blood flow as assessed by stress thallium distribution. J Cardiothorac Vasc Anesth, 2000;14:657-661. [ Links ]
137. Chaney MA - Benefits of neuraxial anesthesia in patients undergoing cardiac surgery. J Cardiothorac Vasc Anesth, 1997;11:808-809. [ Links ]
138. Grass JA - The role of epidural anesthesia and analgesia in postoperative outcome. Anesthesiol Clin North America, 2000;18:407-428. [ Links ]
139. Scott NB, Turfrey DJ, Ray DA et al - A prospective randomized study of the potential benefits of thoracic epidural anesthesia and analgesia in patients undergoing coronary artery bypass grafting. Anesth Analg, 2001;93:528-535. [ Links ]
140. Liu SS, Block BM, Wu CL - Effects of perioperative central neuraxial analgesia on outcome after coronary artery bypass surgery: a meta-analysis. Anesthesiology, 2004;101:153-161. [ Links ]
Dr. Luiz Marcelo Sá Malbouisson
Address: Av. Enéas de Carvalho Aguiar, 44
Divisão de Anestesia 2º andar
ZIP: 05403-000 CEP: São Paulo, Brazil
Submitted for publication January 6, 2005
Accepted for publication May 24, 2005
* Received from Serviço de Anestesiologia e Terapia Intensiva Cirúrgica Instituto do Coração (InCor) HCFMUSP, São Paulo, SP